Manufacture of the ammonium salt of the urea of m-amino-benzoyl-mamino-p-toluyl-1-naphthylamine-4:6:8-trisulphonic acid



Patented Aug. 7, 1934 'Z leit r midi:

. .flgie a fi MKNUFACTUREOF THE AMMONIUM SALT 4 '6 :S-TRISULPHONIC ACID-:.z 1":- ans:- 1 eorge MalcolmwDyson, Cheadle Hulme, and

Arnold. Renshaw, .Manehes'ter, England, assignors to ParkdpDa'vis andCompany, Detroit,

Mich. i i

mutation of Michigan NoDrawmgm-Application January 16, 1929,

fierial No. 333,019

1 12:; =4; 7; I11: i=1... i. y 7 omthe-marketadrug: nownias Bayer .NQu Q7WhEhthas very:considerable therapeutic ;val -ue;;in combating-ediseasescontracted .through .F IYPQ'IL wmQS-a A process foriitsimanufactureis decri e n; thdfatent No 1,2 18,665; i. Info-110wti zrlih drectionsigiven-inithis patenu however, hovegnpt beemablelto produce aproduct-which .appnqaches the usualqactivity of the Bayer No. 205 now onthezmarket vm z'x. 11',

We have, however, found a new process by whichmetpmducea drug of-greateractivity than the said Haven-Nahum. and zeven greater than that of thesimilar product known as Fourneaux 309. We prepare our new product bychlorinating diphenylurea-m-m-dicarboxylic acid so as to chlorinate bothcarboxy groups. This diacid chloride is reacted with the amino bodyobtained by reducing the product of the interaction of m-nitro-p-toluylchloride and a salt of 1- naphthylamine-4 6 8-trisu1phonic acid. Thesolution of the reaction product may be evaporated to dryness in avacuum, the product extracted with methyl alcohol and finallyprecipitated with ethyl alcohol. We may further purify the product byconverting the salt into a lead salt. We can decompose the lead salt toget the free acid and then neutralize this with ammonia. We attributeimportance in securing the greatest efiiciency to our drug to thepurification by this passage through the lead salt, and also weattribute importance to preparing the drug in the form of its salt withammonia.

The chlorination of the diphenyl-urea-m-mdicarboxylic acid can beeffected by treating the free acid or the sodium salt with achlorinating agent, such as thionyl chloride, phosphoric pentachlorideor phosphoric trichloride.

The condensation of the di-acid chloride with the above mentionedreduced reaction product may be effected in the presence of ammoniumacetate or ammonium bicarbonate.

The following example will serve further to illustrate our new process:

Example 200 parts of diphenylurea-3:3-dicarboxylic acid are mixed withthionyl chloride (240 parts) and the mixture heated gently until theacid has gone into solution almost completely. Any excess of the thionylchloride is removed by distillation in vacuo. The gum which remains"forms an intermediateproduct designatedasthe di-acid chloride ofdiphenylurea-m-m'-dicarb'o5 ylicacid having the following probablestructural formula: I

O O-NH SOaNa I S OaNa S O :Na

Stirring is continued until the solution gives only a faint diazoreaction on treating with nitrous acid and resorcinol. The filteredsolution which probably contains the trisodium salt of the urea ofm-amino-benzoyl-m-amino-p-toluyl-l-naphthylamine-:6:8-trisulphonic acidis warmed to 60 C. and a solution of 1000 parts of lead acetate in 8000parts of water containing 1% of ammonia added. The precipitate of leadsalt is collected, washed with water, and treated withsulphuric aciduntil no further precipitate of lead sulphate is obtained. The solutionis filtered from lead sulphate and exactly neutralized with ammonia andevaporated in a vacuum thereby obtaining as the final product theammonium salt of the urea of m-amino-benzoylm -aminop toluyl- 1-naphthylamine-4:6:8-trisulphonic acid which has the following probablestructural formula:

| GONH SOsNH4 /NH I oo OH 3 NH I 503N114 I CONH SOsNH4 GO-NH SOaNHl@somm SOaNH4 Although we have explained and illustrated our invention bymeans of this one example, it will be readily understood by chemiststhat equivalents may be used and equivalent products obtained.

What we claim and desire to secure by Letters Patent is:

1. The ammonium salt of the urea of m-aminobenzoyl m amino ptoluyl-l-naphthylamine- 4:6:8-trisulphonic acid.

2. In the manufacture of a medicinal preparation by condensing thedi-acid chloride of diphenyl urea -m-m'-dicarboxylic acid with thetrisodium salt of m-amino-p-toluyl-l-naphthylamine-4:6:8-trisulphonicacid, the steps which comprise converting the condensation product intoits insoluble lead salt, decomposing the lead salt with sulphuric acidand neutralizing the free acid with ammonia.

3. The process for the manufacture of a urea drug comprising thecondensation of the di-acid chloride by diphenylurea-m-m-dicarboxylicacid with m-amino-p-toluyl-l-naphthylamine-4: 6 8- trisulphonates,precipitating the solution thus obtained with a soluble lead salt,treating the precipitate with sulphuric acid to remove lead sulphate,adding ammonia to the filtrate until neutral and evaporating undervacuum thereby obtaining the ammonium salt of the urea of mamino-benzoylm amino p toluyl 1 naphthylamine-4 6 :8-trisulphonic acid.

4. The process for the manufacture of the urea ofm-amino-benzoyl-m-amino-p-toluyl-1-naphthylamine-4:6:8-trisulphonic acidcomprising the condensation of a salt of diphenylurea-m-m-dicarboxylicacid with m-amino-p-toluyl-l-naphthylamine-4 6 8-trisulphonates.

5. The process for the manufacture of the urea ofm-amino-benzoyl-m-amino-p-toluyl1-naphthylarnine-:6:8-trisulphonic acidcomprising the condensation of the di-acid chloride ofdiphenyluream-m'-dicarboxylic acid withm-amino-ptoluyl-l-naphthylarnine-4 6 8-trisulphonates.

6. The process for the manufacture of a urea drug comprising thecondensation of the di-acid chloride of diphenylurea-m-m'-dicarboxylicacid With the trisodium salt of m-amino-p-toluyl-lnaphthylamine-4 68-trisulphonic acid thereby obtaining the trisodium salt of the urea ofmamino-benzoyl m amino p toluyl 1 naphthylamine-4 6 8-trisulphonic acid.

GEORGE MALCOLM DYSON. ARNOLD. RENSHAW.

